(a) Field of the Invention
The invention relates to a method for the treatment of Alzheimer's disease in a patient based on the cholinergic activity in the brain.
(b) Description of Prior Art
Apolipoprotein E (apo E) functions as a ligand in the process of receptor mediated internalization of lipid-rich lipoproteins, and it is probably also involved in reverse lipid transport (Mahley R. W. et al., 1983, Biochem. Biophys. Acta. 737:197-222). In the central nervous system (CNS), apoE plays a central role in the mobilization and redistribution of cholesterol and phospholipid during membrane remodeling associated with synaptic plasticity (Poirier J. et al., 1991, Mol. Brain. Res., 9:191-195; Poirier J. et al., 1991, Mol. Brain. Res., 11:97-106; Poirier J. et al., 1993, Neuroscience, 55:81-90). The importance of apoE in the brain is further underscored by the absence of other key plasma apolipoproteins such as apo A1 and apo B (Roheim P. S. et al., 1979, Proc. Natl. Acad. Sci., 76:4646-4649) in this tissue. ApoE mRNA is found predominantly in astrocytes in the CNS.
The apoE gene on chromosome 19 has three common alleles (E2, E3, E4), which encode three major apoE isoforms. Recently, the frequency of the apoE4 allele was shown to be markedly increased in sporadic (Poirier J. et al., 1993, Apolipoprotein E phenotype and Alzheimer's Disease, Lancet, 342:697-699; Noguchi S. et al., 1993, Lancet (letter), 342:737) and late onset familial Alzheimer's disease (AD) (Corder E. H. et al., 1993, Science, 261:921-923; Payami H. et al., 1993, Lancet (letter), 342:738). A gene dosage effect was observed in both sporadic and familial cases (i.e. as age of onset increases, E4 allele copy number decreases). Women, who are generally at a greater risk of developing Alzheimer's disease, show increased E4 allele frequency when compared to age matched men.
Preliminary studies have shown that apoE mRNA levels are relatively unchanged (Poirier J. et al., 1991, In: Basic and therapeutic strategies in Alzheimer's and Parkinsons's diseases, T. Nagatsu, F. Abraham. eds., New York, Plenum Press, 191-194) in post-mortem brains of AD patients. These results were obtained from patients whose genotypes were undetermined.
It would be highly desirable to be provided with means to determine the cholinergic activity in the brain of Alzheimer's disease patients to determine if cholinomimetics-based therapies should be carried out.